J Immunother Cancer: first published as 10.1136/jitc-2021-004374 on 16 February 2022. Downloaded from http://jitc.bmj.com/ on July 17, 2023 at Sant Paul Hospital Consortia. Protected by Open access Short report Prognostic effect of body mass index in patients with advanced NSCLC treated with chemoimmunotherapy combinations Alessio Cortellini ‍ ‍ ,1 Biagio Ricciuti ‍ ‍ ,2 Victor R Vaz,2 Davide Soldato,3 Joao V Alessi ‍ ‍ ,2 Filippo G Dall’Olio,3 Giuseppe L Banna,4 Sethupathi Muthuramalingam,5 Samuel Chan,6 Margarita Majem ‍ ‍ ,7 Aida Piedra,7 Giuseppe Lamberti ‍ ‍ ,8 Elisa Andrini,8 Alfredo Addeo,9 Alex Friedlaender,9 Francesco Facchinetti,10 Teresa Gorría,11 Laura Mezquita ‍ ‍ ,12 Delphine Hoton,13 Lacroix Valerie,14 Frank Aboubakar Nana,15 James Artingstall,16 Charles Comins,16 Massimo Di Maio,17 Andrea Caglio,17 Judith Cave,18 Hayley McKenzie,18 Thomas Newsom-­Davis,19 Joanne S Evans,1 Marcello Tiseo,20,21 Antonio D'Alessio,1,22 Claudia A M Fulgenzi,1,23 Benjamin Besse,3,24 Mark M Awad ‍ ‍ ,2 David J Pinato ‍ ‍ 1,25 To cite: Cortellini A, Ricciuti B, ABSTRACT patients with cancer, with positive implications Vaz VR, et al. Prognostic effect Introduction It has been recognized that increasing body with regard to clinical benefit from immune of body mass index in patients with advanced NSCLC treated mass index (BMI) is associated with improved outcome from checkpoint inhibitors (ICIs).1–3 In patients with immune checkpoint inhibitors (ICIs) in patients with various non-­small cell lung cancer (NSCLC), baseline with chemoimmunotherapy copyright. malignancies including non-­small cell lung cancer (NSCLC). obesity is associated with an incremental survival combinations. Journal for ImmunoTherapy of Cancer However, it is unclear whether baseline BMI may influence benefit with programmed death-­ 1 (PD-­1)/ 2022;10:e004374. doi:10.1136/ outcomes from first-­line chemoimmunotherapy combinations. Methods In this international multicenter study, we programmed death-­ ligand 1 (PD-­ L1) inhib- jitc-2021-004374 evaluated the association between baseline BMI, itors compared with normal-­ weight patients, ► Additional supplemental progression-­free survival (PFS) and overall survival (OS) a finding confirmed across different treat- material is published online only. in a cohort of patients with stage IV NSCLC consecutively ment lines and levels of PD-­L1 tumor expres- To view, please visit the journal treated with first-­line chemoimmunotherapy combinations. sion.4 5 In a prior study evaluating patients with online (http://​dx.d​ oi.​org/​10.​ BMI was categorized according to WHO criteria. advanced NSCLC treated with either first-­line 1136/j​ itc-​2021-0​ 04374). Results Among the 853 included patients, 5.3% were pembrolizumab monotherapy or standard underweight; 46.4% were of normal weight; 33.8% were chemotherapy, we showed that the positive Accepted 11 January 2022 overweight; and 14.5% were obese. Overweight and obese effect of body mass index (BMI) on oncolog- patients were more likely aged ≥70 years (p=0.00085), never smokers (p<0.0001), with better baseline Eastern Cooperative ical outcomes was restricted to immunotherapy Oncology Group—Performance Status (p=0.0127), and had recipients, lending further credence to the view lower prevalence of central nervous system (p=0.0002) and that obesity may exert an immune modulatory liver metastases (p=0.0395). Univariable analyses showed a rather than a simply prognostic role.6 significant difference in the median OS across underweight Considerable research efforts are under way (15.5 months), normal weight (14.6 months), overweight to identify tumorous and host determinants of (20.9 months), and obese (16.8 months) patients (log-­rank: response and survival in the context of chemo- p=0.045, log rank test for trend: p=0.131), while no difference immunotherapy combinations, which have was found with respect to the median PFS (log-­rank for trend: significantly improved the first-­line treatment © Author(s) (or their p=0.510). Neither OS nor PFS was significantly associated employer(s)) 2022. Re-­use with baseline BMI on multivariable analysis. landscape of NSCLC7 8; however, to date, there permitted under CC BY-­NC. No Conclusions In contrast to what was observed in the context is no clear evidence about the role of baseline commercial re-­use. See rights BMI in this setting. of chemotherapy-­free ICI-­based regimens, baseline BMI does and permissions. Published by BMJ. not affect clinical outcomes from chemoimmunotherapy combinations in patients with advanced NSCLC. For numbered affiliations see end of article. METHODS Correspondence to INTRODUCTION In this international multicenter study, we Dr Alessio Cortellini; Increasing evidence suggests the presence of evaluated the association between base- ​alessiocortellini@​gmail.​com an obesity-­ driven proinflammatory state in line BMI and clinical outcomes in a cohort Cortellini A, et al. J Immunother Cancer 2022;10:e004374. doi:10.1136/jitc-2021-004374 1 J Immunother Cancer: first published as 10.1136/jitc-2021-004374 on 16 February 2022. Downloaded from http://jitc.bmj.com/ on July 17, 2023 at Sant Paul Hospital Consortia. Protected by Open access Table 1 Patients’ characteristics at baseline for the overall cohort and according to body mass index WHO categories Overall (%) Underweight (%) Normal weight (%) Overweight (%) Obese (%) P value N=853 N=45 N=396 N=288 N=124 Age (years), n (%)  Median 65 59 63 67 66 0.0085  Range 19–88 40–79 19–88 35–87 36–80  <70 593 (69.5) 38 (84.4) 288 (72.7) 183 (63.5) 84 (67.7)  ≥70 260 (30.5) 7 (15.6) 108 (27.3) 105 (36.5) 40 (32.3) Gender, n (%)  Female 338 (39.6) 18 (40.0) 141 (35.6) 119 (41.3) 60 (48.4) 0.0719  Male 515 (60.4) 27 (60.0) 255 (64.4) 169 (58.7) 64 (51.6) ECOG-­PS, n (%)  0–1 633 (75.0) 28 (62.2) 282 (71.8) 227 (80.2) 96 (78.0) 0.0127  ≥2 211 (25.0) 17 (37.8) 111 (28.2) 56 (19.8) 27 (22.0)  Missing 9 – 3 5 1 Histology, n (%)  Adenocarcinoma 679 (79.6) 36 (80.0) 312 (78.8) 231 (80.2) 100 (80.6) 0.7143  Squamous 115 (13.5) 5 (11.1) 52 (13.1) 43 (14.9) 15 (12.1)  Carcinoma NOS/others 59 (6.9) 4 (8.9) 32 (8.1) 14 (4.9) 9 (7.3) Smoking status, n (%)  Never smokers 82 (9.6) 2 (4.4) 35 (8.8) 27 (9.4) 18 (14.5) <0.0001  Former smokers 598 (70.3) 26 (57.8) 263 (66.4) 213 (74.5) 96 (77.4)  Current smokers 171 (20.1) 17 (37.8) 98 (24.7) 46 (16.1) 10 (8.1)  Missing 2 – – 2 – CNS metastases, n (%) copyright.  No 657 (77.4) 24 (53.3) 298 (75.8) 236 (82.2) 99 (79.8) 0.0002  Yes 192 (22.6) 21 (46.7) 95 (24.2) 51 (17.8) 25 (20.2)  Missing 4 – 3 1 – Bone metastases, n (%)  No 520 (61.2) 23 (51.1) 236 (60.1) 181 (63.1) 80 (64.5) 0.3701  Yes 329 (38.8) 22 (48.9) 157 (39.9) 106 (36.9) 44 (35.5)  Missing 4 – 3 1 1 Liver metastases, n (%)  No 731 (86.1) 33 (73.3) 336 (85.5) 250 (87.1) 112 (90.3) 0.0395  Yes 118 (13.9) 12 (26.7) 57 (14.5) 37 (12.9) 12 (9.7)  Missing 4 0 3 1 – PD-­L1 TPS, n (%)  <1% 383 (44.9) 19 (42.2) 178 (44.9) 136 (47.2) 50 (40.3) 0.4704  1%–49% 281 (32.9) 13 (28.9) 134 (33.8) 95 (33.0) 39 (31.5)  ≥50% 140 (16.4) 11 (24.4) 66 (16.7) 39 (13.5) 24 (19.4)  Not available 49 (5.7) 2 (4.4) 18 (4.5) 18 (6.2) 11 (8.9) EGFR mutational status, n (%)  Wild type 761 (89.2) 40 (88.9) 353 (89.1) 255 (88.5) 113 (91.1) 0.8042  Mutant 18 (2.1) – 9 (2.3) 8 (2.8) 1 (0.8)  Unknown 74 (8.7) 5 (11.1) 34 (8.6) 25 (8.7) 10 (8.1)  ALK molecular status, n (%)  Wild type 777 (91.1) 40 (88.9) 362 (91.4) 261 (90.6) 114 (91.9) 0.9176  Unknown 76 (8.9) 5 (11.1) 34 (8.6) 27 (9.4) 10 (8.1) ROS-­1 molecular status, n (%)  Wild type 687 (80.5) 36 (80.0) 319 (80.6) 228 (79.2) 104 (83.9) 0.7999  Unknown 166 (19.4) 9 (20.0) 77 (9.4) 60 (20.8) 20 (16.1) Continued 2 Cortellini A, et al. J Immunother Cancer 2022;10:e004374. doi:10.1136/jitc-2021-004374 J Immunother Cancer: first published as 10.1136/jitc-2021-004374 on 16 February 2022. Downloaded from http://jitc.bmj.com/ on July 17, 2023 at Sant Paul Hospital Consortia. Protected by Open access Table 1 Continued KRAS molecular status, n (%)  Wild type 338 (39.6) 14 (31.1) 173 (43.7) 114 (39.6) 37 (29.8) 0.0011  Mutant 226 (26.5) 14 (31.1) 85 (21.5) 75 (26.0) 52 (41.9)  Unknown 289 (33.9) 17 (37.8) 138 (34.8) 99 (34.4) 35 (28.2) STK11 molecular status, n (%)  Wild type 247 (29.0) 9 (20.0) 115 (29.0) 86 (29.9) 37 (29.8) 0.7273  Mutant 91 (10.7) 5 (11.1) 39 (9.8) 30 (10.4) 17 (13.7)  Unknown 515 (60.4) 31 (68.9) 242 (61.1) 172 (59.7) 70 (56.5) KEAP-­1 molecular status, n (%)  Wild type 244 (28.6) 12 (26.7) 105 (26.5) 84 (29.2) 43 (34.7) 0.4988  Mutant 67 (7.9) 2 (4.4) 36 (9.1) 19 (6.6) 10 (8.1)  Unknown 542 (63.5) 31 (68.9) 255 (64.4) 185 (64.2) 71 (57.3) TP53 molecular status, n (%)  Wild type 233 (27.3) 17 (37.8) 102 (25.8) 72 (25.0) 42 (33.9) 0.2687  Mutant 211 (24.7) 9 (20.0) 105 (26.5) 73 (25.3) 24 (19.4)  Unknown 409 (47.9) 19 (42.2) 189 (47.7) 143 (49.7) 58 (46.8) Median TMB (mut/megabase)  Median (range) 9.1 (1.0– 12.2 (5.3–36.5) 9.1 (1.2–67.6) 8.4 (1.0–25.1) 8.4 (1.3–25.1) 0.1590 67.6)  <10 148 (59.7) 3 (27.3) 68 (60.2) 49 (61.2) 28 (63.6)  ≥10 100 (40.3) 8 (72.7) 45 (39.8) 31 (38.7) 16 (36.4)  Available patients 248 11 113 80 44 Other potentially targetable oncogenes*  Mutant 61 (7.1) 1 (2.2) 31 (7.8) 23 (7.9) 6 (4.8) – copyright. Regimen Pembrolizumab/histology-­based chemotherapy 825 (96.7) 44 (97.8) 387 (97.7) 276 (95.8) 118 (95.2) – Atezolizumab–bevacizumab/platinum doublet 10 (1.2) – 2 (0.5) 6 (2.1) 2 (1.6) Atezolizumab/histology-­based chemotherapy 18 (2.1) 1 (2.2) 7 (1.8) 6 (2.1) 4 (3.2) *Includes HER2 (available for 466 patients), MET (available for 477 patients), BRAF (available for 526 patients) and RET (available for 448 patients). ALK, anaplastic lymphoma kinase; CNS, central nervous system; ECOG-­PS, Eastern Cooperative Oncology Group—Performance Status; EGFR, epidermal growth factor receptor; PD-­L1, programmed death-­ligand 1; TMB, tumor mutational burden; TPS, Tumor Proportion Score. Figure 1 Kaplan-­Meier survival estimates. (A) Overall survival: underweight: 15.5 months (95% CI 8.8 to 15.5, 20 events), normal weight: 14.6 months (95% CI 13.1 to 17.2, 207 events), overweight: 20.9 months (95% CI 17.3 to 28.7, 116 events), obese: 16.8 months (95% CI 12.5 to 23.2, 64 events). (B) Progression-­free survival: underweight: 6.9 months (95% CI 4.0 to 14.2, 30 events), normal weight: 6.6 months (95% CI 5.8 to 7.3, 283 events), overweight: 8.4 months (95% CI 7.2 to 9.7, 182 events), obese: 7.2 months (95% CI 6.0 to 8.6, 87 events). Cortellini A, et al. J Immunother Cancer 2022;10:e004374. doi:10.1136/jitc-2021-004374 3 J Immunother Cancer: first published as 10.1136/jitc-2021-004374 on 16 February 2022. Downloaded from http://jitc.bmj.com/ on July 17, 2023 at Sant Paul Hospital Consortia. Protected by Open access Table 2 Fixed multivariable analysis for risk of disease progression (PFS) and death (OS) PFS OS Variable (comparator) aHR (95% CI), P value aHR (95% CI), P value Body mass index WHO categories  Underweight 0.90 (0.61 to 1.33), 0.6261 0.87 (0.54 to 1.40), 0.5844  (Normal weight) 1 1  Overweight 0.83 (0.68 to 1.01), 0.0676 0.79 (0.62 to 1.01), 0.0587  Obese 1.04 (0.81 to 1.33), 0.7214 0.99 (0.74 to 1.32), 0.9601 PD-­L1 TPS  (<1%) 1 1  1%–49% 0.92 (0.77 to 1.12), 0.4424 1.04 (0.83 to 1.30), 0.7288  ≥50% 0.63 (0.48 to 0.82), 0.0008 0.73 (0.53 to 1.01), 0.0547  Not available 0.65 (0.43 to 0.96), 0.0317 0.81 (0.52 to 1.29), 0.3658 Histology  (Adenocarcinoma) 1 1  Squamous cell carcinoma 1.32 (1.03 to 1.70), 0.0246 1.39 (1.05 to 1.86), 0.0231  Carcinoma NOS/others 1.44 (1.05 to 1.97), 0.0207 1.43 (0.99 to 2.07), 0.0566  ECOG-­PS  ≥2 vs 0–1 1.36 (1.12 to 1.64), 0.0013 1.93 (1.55 to 2.41), <0.0001 Sex  Male versus female 1.12 (0.95 to 1.34), 0.1656 1.10 (0.89 to 1.36), 0.3462 Age  ≥70 vs <70 years old 1.20 (1.01 to 1.45), 0.0484 1.27 (1.01 to 1.58), 0.0337 Smoking status copyright.  (Never smoker) 1 1  Former smoker 0.89 (0.68 to 1.17), 0.4363 1.18 (0.84 to 1.65), 0.3386  Current smoker 0.82 (0.59 to 1.14), 0.2508 1.26 (0.84 to 1.89), 0.2565 CNS metastases  Yes versus no 1.31 (1.07 to 1.60), 0.0082 1.25 (0.98 to 1.59), 0.0612 Bone metastases  Yes versus no 1.23 (1.03 to 1.46), 0.0198 1.26 (1.02 to 1.54), 0.0272 Liver metastases  Yes versus no 1.49 (1.18 to 1.88), 0.0006 1.59 (1.21 to 2.09), 0.0008 838 patients included due to missing values. aHR, adjusted HR; CNS, central nervous system; ECOG-­PS, Eastern Cooperative Oncology Group—Performance Status; OS, overall survival; PD-­ L1, programmed death-­ligand 1; PFS, progression- free survival. of patients with stage IV NSCLC treated with first-­line criteria V.1.1. PFS and OS were measured from treatment chemoimmunotherapy combinations. initiation to disease progression and/or death. Patients In total, 15 institutions across seven countries partici- without documented disease progression were censored pated in the study (online supplemental table 1) and on the date of last imaging follow-­up. retrospectively included patients treated from December 2014 to August 2021, with data cut-­off in November 2021. Evaluation of baseline BMI Patients with oncogene-­ addicted disease previously Patients’ BMI was calculated using the formula of treated with targeted agents only were considered weight/height2 (kilogram/square meter) and catego- eligible. Clinical endpoints included overall survival (OS) rized according to the WHO categories: underweight and progression-­free survival (PFS). Tumor imaging was (BMI <18.5), normal weight (18.5≤BMI≤24.9), overweight assessed at baseline and during treatment at participating (25≤BMI≤29.9), and obese (BMI ≥30). Weight and height institutions, with a frequency of 8–12 weeks according to were retrieved from patient medical records at baseline local practice. Investigators from participating centers and derived within 30 days of treatment initiation. independently reviewed disease response following First, we evaluated the distribution of patients’ char- Response Evaluation Criteria in Solid Tumors (RECIST) acteristics across BMI subgroups, in order to explore 4 Cortellini A, et al. J Immunother Cancer 2022;10:e004374. doi:10.1136/jitc-2021-004374 J Immunother Cancer: first published as 10.1136/jitc-2021-004374 on 16 February 2022. Downloaded from http://jitc.bmj.com/ on July 17, 2023 at Sant Paul Hospital Consortia. Protected by Open access possible associations between baseline BMI and clini- 281 (32.9%), and <1% in 383 (44.9%) patients, respec- copathological features. Subsequently, we assessed the tively. Most of the patients were epidermal growth factor impact of baseline BMI on outcome using univariable receptor (762, 89.2%), anaplastic lymphoma kinase (777, analysis. Considering the results of the univariable anal- 91.1%), and ROS proto-­oncogene 1 (687, 80.5%) wild ysis, we then used fixed multivariable regression models type. Other molecular findings relevant for ICI outcomes to further validate our findings. Covariates were chosen were also reported (when available). on a clinical prioritization basis, in view of their known Several baseline clinicopathological features were prognostic role, including PD-­ L1 tumor expression significantly different across BMI categories. Overweight (≥50% vs 1%–49% vs negative vs not available), primary and obese patients were more likely aged ≥70 years tumor histology (adenocarcinoma vs squamous cell carci- (p=0.00085) and never smokers (p<0.0001), with better noma vs carcinoma not otherwise specified-/others), baseline ECOG-­ PS (p=0.0127) and lower prevalence Eastern Cooperative Oncology Group—Performance of liver metastases (p=0.0395). Prevalence of baseline Status (ECOG-­PS, 0–1 vs ≥2), sex (male vs female), age CNS metastases was also different across BMI categories (<70 vs ≥70 years old), smoking status (current smokers (p=0.0002), with the lowest prevalence reported for the vs former smokers vs never smokers), presence of central overweight subgroup (17.8%), as well as the distribu- nervous system (CNS) metastases (yes vs no), bone metas- tion of the Kirsten rat sarcoma virus (KRAS) mutational tases (yes vs no), and liver metastases (yes vs no). status (p=0.0011), with the highest prevalence of mutant Considering the incremental benefit reported with ICIs patients within the obese subgroup (41.9%). for obese patients over normal-­weight patients in PD-­L1 With a median follow-­up of 17.5 months (95% CI 15.9 selected populations,5 6 we added two exploratory anal- to 18.7), the median PFS and OS of the entire cohort yses including patients with PD-­L1 negative and positive were 7.2 months (95% CI 6.7 to 7.8, 582 events) and 16.8 tumors, and with PD-­L1 high (≥50%) and low (1%–49%) months (95% CI 15.2 to 19.3, 407 events), respectively. tumor expression, respectively. An additional ancillary The median OS across underweight, normal weight, analysis including only patients with an ECOG-­ PS of overweight, and obese patients were 15.5 months 0–1 was also performed. In all the regression analyses, (95% CI 8.8 to 15.5, 20 events), 14.6 months (95% CI 13.1 normal-­weight patients were considered as the compar- to 17.2, 207 events), 20.9 months (95% CI 17.3 to 28.7, ator group. 116 events), and 16.8 months (95% CI 12.5 to 23.2, 64 events), respectively (log rank: p=0.045, log-­rank test for copyright. Statistical analysis trend: p=0.131; figure 1A), while the median PFS across Baseline patients’ characteristics were reported with underweight, normal weight, overweight and obese descriptive statistics as appropriate. The χ2 and test was patients were 6.9 months (95% CI 4.0 to 14.2, 30 events), used to compare categorical variables. PFS/OS were eval- 6.6 months (95% CI 5.8 to 7.3, 283 events), 8.4 months uated and compared using the Kaplan-­Meier method, the (95% CI 7.2 to 9.7, 182 events), and 7.2 months (95% CI log-­rank test, and the log-­rank test for trend. Duration of 6.0 to 8.6, 87 events), respectively (log rank: p=0.123, log follow-­up was calculated according to the reverse Kaplan-­ rank test for trend: p=0.510; figure 1B). Meier method. Cox proportional hazards regression was Table 2 reports the multivariable analyses for PFS and used for the multivariable analysis of PFS and OS and to OS. No association was confirmed between baseline BMI compute the HRs with 95% CIs. Missing values for clini- and clinical outcomes. PD-­L1 tumor expression, ECOG-­ copathological characteristics included in the regression PS, primary tumor histology, age, CNS, and bone and analyses were excluded from the descriptive analysis and liver metastases were confirmed significant determinants the multivariable models. All p values were two-­sided and of PFS, while ECOG-­PS, primary tumor histology, age, CIs set at the 95% level, with significance predefined to bone and liver metastases were confirmed significant be at <0.05. All statistical analyses were performed using determinants for OS. the MedCalc Statistical Software V.20 (MedCalc Software, Online supplemental figure 1 and online supplemental Ostend, Belgium; https://www.medcalc.org; 2021). figure 2 summarize the exploratory analyses including patients with PD-­L1 negative and positive tumors, and with PD-­ L1 of ≥50% and 1%–49% tumor expression, RESULTS according to which baseline BMI was not associated After the exclusion of 26 patients due to missing BMI with clinical outcomes in any of the PD-­L1 expression data, 853 patients were included in the present analysis. subgroups. Characteristics of the study population stratified by WHO The ancillary analysis including only patients with a BMI subgrouping are summarized in table 1. good PS (ECOG-­PS 0–1) is summarized in online supple- In total, 45 patients (5.3%) were underweight; 396 mental figure 3; no association between baseline BMI and (46.4%) were normal weight; 288 (33.8%) were overweight; OS/PFS was confirmed. and 124 (14.5%) were obese. A total of 211 patients had a baseline ECOG-­PS of ≥2 (25.0%). PD-­L1 tumor expression DISCUSSION was evaluable in 804 patients (94.2%), showing a Tumor In this study, we did not find any significant association Proportion Score of ≥50% in 140 (16.4%), 1%–49% in between baseline BMI and clinical outcomes in patients Cortellini A, et al. J Immunother Cancer 2022;10:e004374. doi:10.1136/jitc-2021-004374 5 J Immunother Cancer: first published as 10.1136/jitc-2021-004374 on 16 February 2022. Downloaded from http://jitc.bmj.com/ on July 17, 2023 at Sant Paul Hospital Consortia. Protected by Open access with NSCLC treated with first-­line chemoimmunotherapy immunotherapy and chemotherapy, the lack of central- combinations, regardless of PD-­L1 tumor expression. ized data/imaging review, and incomplete molecular The addition of chemotherapy to ICI is known to profile for all the patients, our study provides a powered enhance tumor antigenicity and can improve treatment analysis and reliable evidence about the absence of efficacy. This changing algorithm has led to the shifting a significant role for the baseline BMI in this setting. of some of the associative paradigms we observed with As additional limitation, the lack of comorbidity data, chemotherapy-­ free, ICI-­based regimens. For instance, especially those closely linked to dysmetabolism, such our group recently showed that a previous antibiotic as cardiopulmonary diseases, hypertension, diabetes therapy does not impair treatment outcomes in patients mellitus, and dyslipidemia, also needs to be mentioned. with NSCLC treated with chemoimmunotherapy combi- Our findings suggest that, in contrast to what has been nations, as reported with single-­agent ICI instead.9 10 The reported in the context of single-­agent ICI, baseline BMI absence of a BMI-­dependent effect on clinical outcome should not be taken into consideration when counseling mirrors these findings and highlights how the host deter- patients with NSCLC for a first-­line chemoimmunotherapy. minants of benefit from ICI might have different roles depending on the specific treatment modality. In the Author affiliations 1 context of single-­agent ICI regimens, obesity has been Department of Surgery and Cancer, Imperial College London, London, UK 2 Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, interpreted as a driver of reduced responsivity of periph- Massachusetts, USA eral T cells, due to the a dysfunctional PD-­1/PD-­L1-­driven 3 Cancer Medicine Department, Gustave Roussy, Villejuif, France immune exhaustion, which could explain the magnified 4 Candiolo Cancer Institute, FPO-­IRCCS, Candiolo, Italy 5 effect of PD-­1/PD-­L1 inhibitors in restoring T-­cell activity Oncology Department, United Lincolnshire Hospital NHS Trust, Lincoln, UK 6 in obese individuals.3 The addition of the chemotherapy Oncology Department, Queen Alexandra University Hospital, Portsmouth Hospitals NHS Trust, Portsmouth, UK backbone could potentially mitigate this mechanism 7 Medical Oncology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, through the enhanced immunogenicity, which minimizes Spain in turn the role of BMI and obesity. 8 Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-­Malpighi Improved outcome has been documented for ever-­ University Hospital, Alma Mater Studiorum University of Bologna, Bologna, Italy 9 smokers in the context of single-­agent ICI.11 Interestingly, Medical Oncology, University Hospital of Geneva, Geneva, Switzerland 10 Biomarqueurs Prédictifs et Nouvelles Stratégies Thérapeutiques en Oncologie, in our population, overweight and obese patients were Université Paris-­Saclay, Institut Gustave Roussy, Inserm, Villejuif, France more likely never smokers. This could be partially linked 11 Department of Medical Oncology, Hospital Clinic, Barcelona, Spain copyright. to the alleged historical association between the smoking 12 Medical Oncology Department, Hospital Clinic de Barcelona, Barcelona, Spain behavior and body weight/fat distribution.12 13 However, 13 Department of Pathology, Cliniques universitaires Saint-­Luc, Bruxelles, Belgium 14 in our population and in chemoimmunotherapy trials Department of Cardiovascular and Thoracic Surgery, IREC, Cliniques Universitaires Saint-­Luc, Bruxelles, Belgium as well, the role of the smoking status as a strong driver 15 Institut de Recherche Expérimentale et Clinique (IREC), Pôle de Pneumologie, ORL of improved outcomes with chemotherapy-­free ICI regi- et Dermatologie (PNEU), Université catholique de Louvain (UCLouvain), Brussels, mens has also been dimensioned.14 Belgium Evidence for a positive prognostic role for a high base- 16 Bristol Haematology and Oncology Centre, Bristol, UK 17 line BMI was already described in patients with NSCLC Department of Oncology, University of Turin and Mauriziano Hospital, Turin, Italy 18 Department of Medical Oncology, University Hospital Southampton NHS treated with first-­ line chemotherapy during the ‘pre-­ Foundation Trust, Southampton, UK ICI era’.15 Several evidence highlights that a systemic 19 Department of Oncology and National Centre for HIV Malignancies, Chelsea and inflammatory overactivation plays a central role as cancer Westminster Hospital, London, UK cachexia mechanism,16 and in an aggressive disease such 20 Department of Medicine and Surgery, University of Parma, Parma, Italy 21 as metastatic lung cancer, baseline nutrition, weight loss, Medical Oncology Unit, University Hospital of Parma, Parma, Italy 22 and performance status were historically considered Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (Milan), Italy closely intertwined.17 From this perspective, the 30-­day 23 Department of Medical Oncology, University Campus Bio-­Medico, Rome, Italy time window for baseline BMI data collection could even 24 School of Medicine, University Paris-­Saclay, Villejuif, France be considered as a partial limitation to our study. 25 Division of Oncology, Department of Translational Medicine, University of Piemonte In previous reports including single-­agent ICI recipients, Orientale, Novara, Italy a linear trend between increasing BMI and incremental benefit was reported, with obese patients experiencing Twitter Alessio Cortellini @ACortelliniMD, Biagio Ricciuti @BiagioMd, Victor R Vaz @victorrvaz, Joao V Alessi @alessi_joao, Margarita Majem @margamajem, the best outcome5 6; in this cohort, overweight patients Giuseppe Lamberti @GLambertiMD, Antonio D'Alessio @A_DAlessioMD, Claudia A are those who achieved the longest survival in absolute M Fulgenzi @FulgenziClaudia, Mark M Awad @DrMarkAwad and David J Pinato @ terms. Importantly, we also found an association between DJPinato increasing BMI and better ECOG-­PS/lower burden of Acknowledgements The authors acknowledge the infrastructure support provided disease, which are major drivers of better outcome with by Imperial Experimental Cancer Medicine Center, Cancer Research UK Imperial Center, and the Imperial College Healthcare NHS Trust Tissue Bank. ICIs,18 with the lowest prevalence of patients with poor performance status for the overweight group. Contributors All authors contributed to the publication according to the ICMJE guidelines for the authorship (study conception and design, acquisition of data, Despite acknowledging several limitations, mainly analysis and interpretation of data, drafting of manuscript, and critical revision). coming from the retrospective design, the lack of All authors read and approved the submitted version of the manuscript (and matched control cohorts receiving first-­line single-­agent any substantially modified version that involves the author’s contribution to the 6 Cortellini A, et al. J Immunother Cancer 2022;10:e004374. doi:10.1136/jitc-2021-004374 J Immunother Cancer: first published as 10.1136/jitc-2021-004374 on 16 February 2022. Downloaded from http://jitc.bmj.com/ on July 17, 2023 at Sant Paul Hospital Consortia. Protected by Open access study). Each author agreed both to be personally accountable for the author’s own Joao V Alessi http://orcid.org/0000-0002-8072-5946 contributions and to ensure that questions related to the accuracy or integrity of Margarita Majem http://orcid.org/0000-0002-9919-7485 any part of the work, even ones in which the author was not personally involved, Giuseppe Lamberti http://orcid.org/0000-0003-3069-7630 are appropriately investigated, resolved, and the resolution documented in the Laura Mezquita http://orcid.org/0000-0003-0936-7338 literature. Mark M Awad http://orcid.org/0000-0003-0928-5244 David J Pinato http://orcid.org/0000-0002-3529-0103 Funding This study was supported in part by the NIHR Imperial College BRC Push for Impact scheme 2019. AD’A is supported by grant funding from the European Association for the Study of the Liver (Andrew Burroughs Fellowship). BR is supported by the Society of Immunotherapy of Cancer-­AstraZeneca Young Investigator Award. DJP is supported by grant funding from the Wellcome Trust REFERENCES 1 Cortellini A, Bersanelli M, Buti S, et al. A multicenter study of body Strategic Fund (PS3416) and from the Associazione Italiana per la Ricerca sul mass index in cancer patients treated with anti-­PD-­1/PD-­L1 immune Cancro (AIRC MFAG Grant ID 25697) and acknowledges support by the NIHR checkpoint inhibitors: when overweight becomes favorable. J Imperial Biomedical Research Centre (BRC), the Imperial Experimental Cancer Immunother Cancer 2019;7:57. Medicine Centre (ECMC) and the Imperial College Tissue Bank. AC is supported by 2 Cortellini A, Bersanelli M, Santini D, et al. Another side of the the NIHR Imperial BRC. association between body mass index (BMI) and clinical outcomes of cancer patients receiving programmed cell death protein-­1 (PD-­1)/ Disclaimer The views expressed are those of the authors and do not necessarily Programmed cell death-­ligand 1 (PD-­L1) checkpoint inhibitors: A reflect those of the National Institute for Health Research or the Department of multicentre analysis of immune-­related adverse events. Eur J Cancer Health and Social Care. 2020;128:17–26. 3 Wang Z, Aguilar EG, Luna JI, et al. Paradoxical effects of obesity Competing interests AC received speaker fees and grant consultancies on T cell function during tumor progression and PD-­1 checkpoint from AstraZeneca, MSD, BMS, Roche, Novartis, and EISAI. GLB received grant blockade. Nat Med 2019;25:141–51. consultancies from AstraZeneca and Astellas Pharma. LM reports receiving 4 Ichihara E, Harada D, Inoue K, et al. 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